Lipase Maturation Factor 1 (Lmf1) Is Induced by Endoplasmic Reticulum Stress Through Activating Transcription Factor 6α (Atf6α) Signaling

Background: Lipase maturation factor 1 (Lmf1) plays an important role in plasma lipid metabolism, but its regulation remains uncharacterized. Results: Endoplasmic reticulum (ER) stress induces Lmf1 expression in cell lines and mouse liver. Atf6 deficiency abolishes, whereas active Atf6 stimulates this response. Conclusion: Lmf1 is an unfolded protein response (UPR) target through Atf6 signaling. Significance: Lmf1 regulation by the UPR suggests a possible role in ER homeostasis. Lipase maturation factor 1 (Lmf1) is a critical determinant of plasma lipid metabolism, as demonstrated by severe hypertriglyceridemia associated with its mutations in mice and human subjects. Lmf1 is a chaperone localized to the endoplasmic reticulum (ER) and required for the post-translational maturation and activation of several vascular lipases. Despite its importance in plasma lipid homeostasis, the regulation of Lmf1 remains unexplored. We report here that Lmf1 expression is induced by ER stress in various cell lines and in tunicamycin (TM)-injected mice. Using genetic deficiencies in mouse embryonic fibroblasts and mouse liver, we identified the Atf6 arm of the unfolded protein response as being responsible for the up-regulation of Lmf1 in ER stress. Experiments with luciferase reporter constructs indicated that ER stress activates the Lmf1 promoter through a GC-rich DNA sequence 264 bp upstream of the transcriptional start site. We demonstrated that Atf6 is sufficient to induce the Lmf1 promoter in the absence of ER stress, and this effect is mediated by the TM-responsive cis-regulatory element. Conversely, Atf6 deficiency induced by genetic ablation or a dominant-negative form of Atf6 abolished TM stimulation of the Lmf1 promoter. In conclusion, our results indicate that Lmf1 is an unfolded protein response target gene, and Atf6 signaling is sufficient and necessary for activation of the Lmf1 promoter. Importantly, the induction of Lmf1 by ER stress appears to be a general phenomenon not restricted to lipase-expressing cells, which suggests a lipase-independent cellular role for this protein in ER homeostasis.